Pemetrexed for advanced non-small cell lung cancer patients with interstitial lung disease.

Kato et al. BMC Cancer 2014, 14:508
http://www.biomedcentral.com/1471-2407/14/508

RESEARCH ARTICLE Open Access

Pemetrexed for advanced non-small cell lung
cancer patients with interstitial lung disease

Motoyasu Kato 1 " Takehito Shukuya 1 *, Fumiyuki Takahashi 1 , Keita Mori 2 , Kentaro Suina 1 , Tetsuhiko Asao 1 ,
Ryota Kanemaru 1 , Yuichiro Honma 1 , Keiko Muraki 1 , Koji Sugano 1 , Rina Shibayama 1 , Ryo Koyama 1 ,
Naoko Shimada 1 and Kazuhisa Takahashi 1

Cancer

Abstract

Background: Non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) need to be
approached carefully given the high incidence of pulmonary toxicity. Pemetrexed (PEM) is the key drug for the
treatment of NSCLC. However, its safety, especially with respect to the exacerbation of ILD, and efficacy in NSCLC
patients with ILD have yet to be established.

Method: We investigated the safety and efficacy of PEM monotherapy in NSCLC patients with or without idiopathic
interstitial pneumonia (IIPs). The medical charts of these patients were retrospectively reviewed.

Results: Twenty-five patients diagnosed as having IIPs (IIPs group) and 88 patients without ILD (non-ILD group)
were treated with PEM monotherapy at Juntendo University Hospital between 2009 and 2013. In the IIPs group, 12
patients were found to have usual interstitial pneumonitis (UIP) on chest computed tomography (CD (UIP group)
and the other 13 patients showed a non-UIP pattern on chest CT (non-UIP IIPs group). Three patients in the IIPs
group (2 in the UIP group and 1 in the non-UIP IIPs group) and 1 in the non-ILD group developed pulmonary
toxicity during treatment (3.5% overall, 12.0% in the IIPs group versus 1.1% in the non-ILD group). Moreover, all 3
patients in the IIPs group died of pulmonary toxicity. Overall survival tended to be longer in the non-ILD group than
in the IIPs group (p = 0.08). Multivariate analyses demonstrated that IIPs was the only significant independent risk
factor for PEM-related pulmonary toxicity.

Conclusion: We found that the incidence of PEM-related pulmonary toxicity was significantly higher amongst
NSCLC patients with IIPs than among those without IIPs. Particular care must be taken when administering PEM to
treat NSCLC patients with IIPs.

Keywords: Non-small cell lung cancer, Pemetrexed, Interstitial pneumonitis, Idiopathic pulmonary fibrosis, Acute
lung injury, Acute exacerbation

Background

Lung cancer is a pulmonary disease with a poor prognosis,
and is frequently associated with interstitial lung disease
(ILD), especially idiopathic interstitial pneumonitis (IIPs).
ILD consists of disorders of known causes as well as dis-
orders of unknown cause. IIPs are most frequent disease
in ILD. Then, ILDs except for IIPs contains many hetero-
geneous diseases like collagen vascular disease related

* Correspondence: mtkatou@juntendo.ac.jp; tshukuya@juntendo.ac.jp
department of Respiratory Medicine, Juntendo University Graduate School
of Medicine, 2-1 -1 , Hongo, 1 1 3-8421 Bunkyo-ku, Tokyo, Japan
Full list of author information is available at the end of the article

(3 BioMed Central

interstitial pneumonia, sarcoidosis, pneumoconiosis, radi-
ation pneumonitis and drug related lung injury.

The incidence of lung cancer in patients with ILD has
been reported to be approximately 15-30%, [1] and its in-
cidence at autopsy in Japanese patients with usual intersti-
tial pneumonitis (UIP) has been reported to be 48.2% (40
cases in total autopsies) [2]. On the other hand, it has been
reported that the prevalence of idiopathic pulmonary fibro-
sis (IPF) in the United States and Japan were estimated to
be 14.0 to 42.7 and 3.44 per 100,000 people, respectively
[3,4]. It is unknown whether the prevalence of IPF and
prevalence of lung cancer in IPF patients are influenced by
ethnic, geographic or cultural factors or not, because there

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Dedication waiver (http://creativecommons.Org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.

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are no reports on direct comparison of incidence and
prevalence rate between Caucasian and Japanese [5].

Non-small cell lung cancer (NSCLC) is a progressive
disease, and hence, NSCLC patients are usually diagnosed
with advanced stage cancer and usually receive chemo-
therapy. Acute lung injury (ALI) and exacerbation of ILD
are known common side effects of chemotherapy, for
which pre-existing pulmonary fibrosis is reported to be
the most significant risk factor. Furthermore, NSCLC
patients with ILD were found to have a greater risk of
developing pulmonary toxicity (ALI/exacerbation of
ILD) as a result of chemotherapy than patients without
ILD, in a prospective study conducted in Japan [6]. Fur-
ther, the incidence of exacerbation of ILD due to
chemotherapy is significantly higher among lung cancer
patients with a UIP pattern on CT findings than among
those with a non-UIP pattern [7]. However, it is unclear
which regimen and anticancer agent presents the lower
or higher risk of pulmonary toxicity for NSCLC patients
with ILD.

It has been reported that the incidence of pulmonary
toxicity in Japanese patients (2%) is higher than in USA
patients (0.3%) in treatment of gefitinib for NSCLC pa-
tients by FDA [8]. Although there are no reports on direct
comparison of pulmonary toxicity induced by cytotoxic
agents among Japanese, non- Asian and Caucasian, the in-
cidence of docetaxel (DTX) -induced pulmonary toxicity is
about 2.1% (6 cases in 276 total patients) in Caucasian [9]
and 4.6% (18 cases in 392 total patients) [10] in Japanese.
And it has been reported that the incidence of bleomycin-
induced lung injury was 0.66% in Japan and 0.01% in glo-
bal cases [11]. Based on these reports, chemo-associated
pulmonary toxicity seemed to be more frequent in Japanese
patients than Caucasian patients, and this ethnic difference
may be explained by genetically. However, so far, there
is no clear scientific evidence which reveal this ethnic
difference.

Pemetrexed (PEM) is an established multi-targeted anti-
folate drug and one of the important anticancer agents
for advanced non-squamous NSCLC (NSqNSCLC) and
malignant pleural mesothelioma (MPM). PEM com-
bined with platinum agents is often used as a first-line
chemotherapeutic agent to treat patients with advanced
NSqNSCLC and MPM [12]. PEM monotherapy is also
an effective second-line treatment for patients with ad-
vanced NSqNSCLC. Hanna et al. studied the efficacy and
safety of PEM monotherapy in American NSqNSCLC pa-
tients and found that the incidence of PEM-induced pul-
monary toxicity was approximately 0.8% (2 cases in total
265 patients), [9] although this was found to be slightly
higher (3.5%, 4 cases in total 114 cases) among Japanese
NSCLC patients [13]. Amongst MPM patients, Kuribayashi
et al. found that the incidence of PEM and cisplatin
(CDDP)-related pulmonary toxicity was 0.9% (8 cases in

total 903 patients) [14]. However, the incidence of PEM-
related pulmonary toxicity in NSCLC patients with IIPs
or IPF is yet to be established. In the study reported
here, we compared the efficacy and safety (with special
regard to pulmonary toxicity) of PEM treatment in ad-
vanced NSCLC patients with IIPs to that in patients
without ILD in Japan.

Methods

Patient selection

Between April 2009 and May 2013, 116 NSCLC patients
were administered PEM monotherapy at Juntendo University
Hospital. Two patients with radiation pneumonitis and 1 pa-
tient with collagen vascular disease associated with interstitial
pneumonitis were excluded from this study. There were
no patients with other known causes of ILD (e.g., sarcoid-
osis, pneumoconiosis, and chronic hypersensitivity pneu-
monitis). Twenty- five NSCLC patients diagnosed as
having IIPs (IIPs group) and 88 patients without ILD,
including IIPs (non-ILD group) were enrolled in this
retrospective cohort study (Figure 1).

Patients found to have an interstitial shadow on a chest
CT scan were enrolled into the IIPs group, and those with-
out an interstitial shadow were entered into the non-ILD
group. Interstitial shadows were defined as reticular
shadow, ground glass opacity, honeycombing, and traction
bronchiectasis. The IIPs group was further divided into
patients with honeycombing with or without traction
bronchiectasis; subpleural, basal predominance; or reticu-
lar abnormality on chest CT (UIP group) and those with
an interstitial shadow without honeycombing on chest
CT (non-UIP IIPs group). The UIP pattern was diag-
nosed based on chest CT features as defined by "An Official
ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary
Fibrosis: Evidence-based Guidelines for Diagnosis and
Management" [5]. Three pulmonologists (MK, TS and
RK) reviewed pretreatment CT and plain X-ray films of
the chest. All patients involved in this trial provided in-
formed consent for use of medical data. This study
protocol was approved by Juntendo University Ethical
Committee and registered under number is 25-408.

Treatment method

Patients were administered 500 mg/m 2 PEM as a 10-minute
intravenous infusion every 3 weeks. Before the treatment
cycle could be started, patients needed to have an absolute
neutrocyte count (ANC) of at least 1,500/mm 3 , a platelet
count of at least 100,000/mm 3 , transaminase values less
than 2.5 times the upper limit of the normal range, and
total serum bilirubin and creatinine levels less than 1.5
times the upper limit of the normal range. Patients in the
PEM arm were asked to take a daily oral folic acid dose of
500 ug beginning approximately one week before the first
dose of PEM and continuing until 3 weeks after the last

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Patients treated with PEM monotherapy at Juntendo University Hospital
between April 2009 and May 2013 (n = 116)

Patient with CVD-IP (n = 1)
and

radiation pneumonitis (n = 2)

EXCLUDED

f

Patients
in IIPs group
(n = 25)

Patients
in UIP group
(n = 13)

Figure 1 Study patients.

1

Patients
in non-ILD group
(n = 88)

1

Patients
in non-UIP IIPs group
(n = 12)

dose of PEM. Vitamin B12 (1 g) was administered by
intramuscular injection approximately 1 week before the
first dose of PEM and was repeated approximately every
9 weeks until discontinuation of PEM [9,13].

Evaluation of response and toxicity

Response Evaluation Criteria in Solid Tumor (RECIST) ver-
sion 1.1 was used to evaluate the response to treatment.
Chest CT was performed after every 2 cycles of PEM in
order to evaluate the change in tumor size. Adverse events
were evaluated until 4 weeks after the completion of
chemotherapy according to Common Terminology Cri-
teria for Adverse Event (CTCAE) version 4.0. Pneumon-
itis, pulmonary fibrosis, and adult respiratory distress
syndrome in CTCAE term were defined as pulmonary
toxicity. We evaluated and compared response, survival,
and toxicities between the IIPs and non-ILD groups,
and in order to evaluate the response and pulmonary
toxicity, we also analyzed patients in both the UIP and
non-UIP IIPs groups.

Statistical method

We used the Chi square test, Fisher s exact test, or
Wilcoxon two-sample test to compare patient characteris-
tics, response to PEM, and the frequency of toxicities, as
appropriate. Logistic regression analysis was used to esti-
mate the risk of pulmonary toxicity. Progression-free sur-
vival (PFS) and overall survival (OS) curves were plotted
using the Kaplan Meier method and the differences in
PFS and OS between IIPs group and non-ILD group were
analyzed using the log-rank test. Univariate and multivari-
ate analyses were performed in order to identify risk fac-
tors for PEM-related pulmonary toxicity. Multivariate
analyses were performed using logistic regression to assess
the relationship between various factors and pulmonary
toxicity.

All ^-values less than 0.05 were considered statistically
significant. All statistical analyses were performed using
JMP ver. 8.0 for Windows (SAS Institute Inc., Cary, NC,
USA).

Results

Patient characteristics

Between April 2009 and May 2013, 25 NSCLC patients
in the IIPs group and 88 patients in the non-ILD group
were administered PEM monotherapy at Juntendo Uni-
versity Hospital and enrolled in this retrospective cohort
study. Of the patients in the IIPs group, 12 with an inter-
stitial shadow and honeycombing on a chest CT scan
were entered into the UIP group and 13 patients with an
interstitial shadow but without honeycombing were en-
tered into the non-UIP IIPs group. The baseline charac-
teristics of all patients and their diagnoses are listed in
Table 1. There were no significant differences in age,
performance status (PS), disease stage, or tumor histology.
There was, however, a significant difference in the gender
distribution between the IIPs and non-ILD groups (23
[92%] versus 41 [46.6%] male patients, p = 0.0001).
Twenty-four (96%) and 49 patients (55.7%) had a smok-
ing history in the IIPs and non-ILD group, respectively
{p = 0.001). Three patients in the IIPs group (12.0%) had
the sensitive epithelial growth factor receptor (EGFR)
mutation (1 in the UIP group [8.3%] and 2 in non-UIP
IIPs group [15.3%]) compared to 28 in the non-ILD
group (31.8%; p = 0.088). A higher proportion of patients
in the non-ILD group than in the IIPs group carried the
sensitive EGFR mutation, although this difference was not
statistically significant.

Efficacy and survival

Treatment response and outcome was not relatively dif-
ferent between two groups. The response rates did not
differ significantly (12.0% in the IIPs group versus 18.1%

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Table 1 Patient characteristics

MPs

Non-ILD

UlP + non- UIP MPs

UIP

Non-UIP MPs

Number of patients

25

12

13

88

Age (year)

Median (range)

69 (58-81)

71 (58-80)

68 (60-81)

70 (35-92)

Gender

Male (%)

23 (92.0)

12 (100)

1 1 (84.6)

41 (46.6)

Smoking History

Yes (%)

24 (96.0)

12 (100)

12 (92.3)

49 (55.7)

Performance status

0-1 (%)

21 (84.0)

10 (83.3)

11 6)

80 (92.0)

Histology

Adenocarcinoma (%)

22 (88.0)

10 (83.3)

12 (92.3)

83 (94.3)

Stage

NIB + IV (%)

19 (76.0)

10 (83.3)

9 (69.2)

73 (82.9)

Line

1/2/3

5/10/10

2/4/6

3/6/4

13/44/31

EGFR mutation

Sensitive (%)

3 (12.0)

1 (8.3)

2 (15.3)

28 (31.8)

in the non-ILD group and 8.3% in the UIP group versus
7.7% in the non-UIP IIPs group). Responses of 2 patients
in the IIPs group and 1 patient in the non-ILD group
were not evaluable. PFS also did not differ significantly
between the IIPs groups and the non-ILD group (me-
dian, 87 days in the IIPs groups versus 98 days in the
non-ILD groups; hazard ratio, 0.84; 95% confidence
interval [CI], 0.52-1.36; p = 0.49; Figure 2A). Further, al-
though there was no significant difference in OS be-
tween the 2 groups (median, 381 days in the IIPs group
versus 670 days in the non-ILD group; hazard ratio,
1.66; 95% CI, 0.93-1.93; p = 0.08), OS tended to be lon-
ger in the non-ILD group (Figure 2B). The disease con-
trol rates differed significantly between the groups
(48.0% in the non-ILD group versus 72.7% in the IIPs
group, p = 0.03 and 25% in the UIP group versus 61.5%
in the non-UIP IIPs group, p = 0.03).

Toxicity

All patients were assessable for toxicities. The principal
grade 3 or 4 toxicities, with the exception of pulmonary
toxicity, are summarized in Table 2. There were no sig-
nificant differences in grade 3 or 4 toxicities between the
2 groups.

Pulmonary toxicity

Pulmonary toxicity was experienced by 2 patients in the
UIP group, and a single patient each in the non-UIP IIPs
and non-ILD groups, making the overall incidence of
pulmonary toxicity associated with PEM 3.5% (Table 3).
The incidence of PEM-related pulmonary toxicity was
significantly higher in the IIPs group than in the non-
ILD group (12.0% versus 1.1%; odds ratio [OR], 11.8;
95% CI, 1.17-119; p = 0.03), and the incidence of pul-
monary toxicity tended to be higher in the UIP group
than in the non-UIP IIPs group (16.7% versus 7.7%; OR,
7.25; 95% CI 0.42-123.69; p = 0.S9). The number of cy-
cles between the first PEM treatment and the occur-
rence of pulmonary toxicity was 3 in 1 case, 2 in 2 cases,

and 1 in 1 case. Chest CT findings at the onset of tox-
icity in the 2 cases of PEM-related pulmonary toxicity in
the IIPs group (a single patient each in the UIP and
non-UIP IIPs groups) showed a diffuse alveolar damage
(DAD) pattern. The DAD pattern consists of new diffuse
and bilateral ground glass opacity (GGO) together with
a reticular shadow in the non-segmental predominance
of lung opacity with new traction bronchiectasis [15,16].
However, the chest CT findings at the onset of pulmon-
ary toxicity in 2 other patients (a single patient each in
the UIP and in the non-ILD groups) revealed a hyper-
sensitivity pneumonitis (HP) pattern (only new GGO)
[15,16]. All 3 patients in the IIPs group and no patients
in non-ILD group died of pulmonary toxicity. Three pa-
tients in the IIPs group received steroid pulse therapy
after the diagnosis of pulmonary toxicity. A single pa-
tient with DAD discovered on chest CT in the non-UIP
IIPs group died of respiratory failure 2 weeks after the
initiation of steroid pulse therapy, and another patient
with HP discovered on chest CT in the UIP group was
administered 500 mg/day methylprednisolone for 3 days
with a gradually reduced dose of oral prednisolone after
steroid pulse therapy. However, in this latter case, ILD
exacerbation recurred when oral prednisolone was ad-
ministered at the dose of 20 mg, and chest CT revealed
a DAD pattern. Although the patient was administered
1 g of methylprednisolone, he died 5 days after the initi-
ation of the second steroid pulse therapy. A further pa-
tient in the UIP group recovered from exacerbation of
ILD after steroid pulse therapy but died of pneumonitis
and respiratory failure 3 months after the onset of this
toxicity. Conversely, for a patient in the non-ILD group,
cessation of PEM therapy alone resulted in an improve-
ment in symptoms and image findings after 1 week. In
all cases, we excluded bacterial pneumonia, pulmonary
embolism, and heart failure by physical examination, la-
boratory and culture findings, or echocardiography. The
results of univariate and multivariate analyses of risk fac-
tors for pulmonary toxicity associated with PEM therapy

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2

B

g o.8-
3

IIPs group median 87 days 95% CI 61.6-112.36
non-ILD group median 98 days 95% CI 58.09-137.9

Hazard ratio 0.84 (95% CI 0.524-1.363 p = 0.49)
+ censored case

Follow up time (days)

IIPs group median 381 days 95% CI 183.4-578.6
non-ILD group median 670 days 95% CI 418.3-921.7

Hazard ratio 1.66 (95% CI 0.93-2.93, p=0.08)
+ censored case

200.00 400.00 600.00 800.00 1000.00 1200.00 1400.00

Follow up time (days)

Figure 2 Kaplan-Meier curves of progression-free survival and overall survival. (A) Kaplan-Meier plot of progression-free survival for
patients with IIPs and non-ILD. (B) Kaplan-Meier plot of overall survival for patients with IIPs and non-ILD.

Table 2 Toxicities (excluded for pulmonary toxicities)

Number of patients

IIPs

25

non-ILD
88

n

%

n

%

AST, ALT

1

4

2

2.2

0.45

Eruption

4

16

4

4.4

0.13

Nausea

1

4

3

3.4

0.63

Allergic fever

0

0

4

4.4

0.63

Neutropenia

3

12

14

15.9

0.85

Leukocytopenia

2

8

7

8

0.68

Anemia

0

0

2

2.2

0.92

Thorombocytopenia

0

0

1

1.1

0.50

Febrile neutrocytopenia

0

0

1

1.1

0.50

Table 3 Pulmonary toxicity

IIPs

Non-IIPs Total

UIP + non-
UIP IIPs

UIP

Non-UIP IIPs

n %

n %

n %

n % N %

Number of
Patients

25

12

13

88 113

Pulmonary
toxicity

3 12

2 16.7

1 7.7

1 1.1 4 3.5

Grade 5 ILD

3

2

1

0 3

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are shown in Tables 4 and 5 IIPs was significantly associ-
ated with pulmonary toxicity (OR, 11.8; 95% CI, 1.17-
119.6; p = 0.03). Multivariate analyses were performed
using six variables (age, gender, smoking history, per-
formance status, number of treatment lines, and the
presence of IIPs) and revealed that only IIPs (OR, 34.37;
95% CI, 1.64-45566.21; p = 0.019) was a significant inde-
pendent risk factor.

Discussion

To our knowledge, this is the first study to evaluate and
compare the safety and efficacy of PEM monotherapy
between NSCLC patients with IIPs and without ILD.
Previous reports of PEM-induced pulmonary toxicity are
summarized in Table 6 [17-22]. There was only a single
case of PEM monotherapy-induced pulmonary toxicity.
As a result, the risk factors for PEM monotherapy-
induced pulmonary toxicity were unclear, especially with
regard to the presence of ILD. Our findings indicate that
ILD is a risk factor for PEM monotherapy-induced pul-
monary toxicity. We suggest therefore that the presence
of ILD should be addressed before treating NSCLC pa-
tients with PEM monotherapy, as this is frequently found
to be coincident with this malignancy. Of the 8 patients in
previous studies, treatment with oral steroids improved
the symptoms and image findings in 2 cases. Although
other patients received intravenous steroid pulse therapy,

4 of them died due to a worsening of respiratory failure.
Amongst the cases we report here, 3 patients in the IIPs
group were administered steroid pulse therapy, but 2 of
them died of respiratory failure and the other recovered
from exacerbation of ILD, but died when it subsequently
recurred. Only 1 patient, in the non-ILD group, recovered
as a result of drug withdrawal alone. It seems therefore
that the prognosis after pulmonary toxicity is worse for
patients with pre-existing ILD before chemotherapy.

Our results indicate that the overall incidence of PEM-
related pulmonary toxicity is 3.5%, which is very similar
to the incidence given in previous Japanese reports. [13]
However, the incidence of pulmonary toxicity amongst
patients with IIPs was 12.0%, and it is particularly note-
worthy that the incidence of pulmonary toxicity in pa-
tients with a UIP pattern on chest CT was 16.7%.
Consistent with these findings, it has been reported that
the incidence of the exacerbation of ILD due to chemo-
therapy was significantly higher amongst lung cancer pa-
tients with a UIP pattern on CT than among those with
a non-UIP pattern [7].

We evaluated adverse events until 4 weeks after the
completion of chemotherapy. Pulmonary toxicity did not
occur during 4 weeks after pemetrexed treatment with
EGFR-TKI. Pulmonary toxicity also did not occurred
during 2 weeks after cessation of pre-treatment EGFR-
TKI. Therefore, we suppose PEM-induced pulmonary

Table 4 Univariate analysis of risk factors associated with PEM-related pulmonary toxicity

Number of patients

Overall

Pulmonary toxicity

non-Pulmonary toxicity

Odds ratio

95% CI

P

Number of patients

113

4

109

Age (year)

0.36

0.03-3.62

0.62

<71

60

3

57

^71

53

1

52

Gender

2.36

0.23-23.41

0.63

Female

49

1

48

Male

64

3

61

Smoking history

1.80

0.18-17.9

1.00

No

42

1

41

Yes

71

3

68

Performance status

0.34

0.28-31.0

0.37

0-1

101

3

98

2-3

11

1

10

Number of line

0.57

0.05-5.71

1.00

1-2

72

3

69

3-

41

1

40

IIPs

11.8

1.17-119.6

0.03*

No

88

1

87

Yes

25

3

22

^Statistically significant by Fisher's exact test.

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Table 5 Multivariate Analysis of Risk Factors Associated
with PEM-induced ILD

Odds ratio 95% CI P

Variable

Age (<71 vs ^71)

0.20

0.003-2.52

0.23

Gender (Female vs Male)

1.32

0.03-53.99

0.86

Smoking history (no vs yes)

4.68

0.09-443.12

0.44

Performance status (0-1 vs 2-3)

0.17

0.005-5.38

0.28

Number of line (1-2 vs 3-)

0.23

0.009-2.83

0.27

MPs (no vs yes)

34.37

1.64-4566.21

0.019*

^Statistically significant by Logistic regression analysis.

toxicity was not affected by EGFR-TKI treatment in our
research.

As is the case for PEM, DTX monotherapy is frequently
used as a second-line treatment for NSCLC Tamiya et al
reported that the incidence of pulmonary toxicity after
DTX therapy was 4.6% (18 cases in 392 total patients),
and a pre-existing interstitial change on chest CT was as-
sociated with a higher incidence of pulmonary toxicity
(25.9%, 17 cases in 68 patients with NSCLC and intersti-
tial shadow on chest CT) [10]. When taken together, these
findings indicate that PEM may be suitable as a standard
second-line treatment option for NSqNSCLC patients
with IIPs. However, it is unclear which regimen and anti-
cancer agent presents the lowest risk of pulmonary tox-
icity for NSCLC patients with ILD, because most research
is retrospective and includes only a relatively small num-
ber of patients. A prospective, larger study is warranted to

determine the appropriate regimen for advanced NSCLC
patients with ILD.

We found no significant difference in PFS with respect
to interstitial changes on chest CT, although OS in the
non-ILD group tended to be longer than in the IIPs group.
One possible explanation for the latter is that more pa-
tients had a sensitive EGFR mutation in the non-ILDs
group than in the IIPs groups.

This analysis has several limitations. First, the diagno-
sis of preexisting ILD and exacerbation of ILD was based
on chest CT and laboratory findings, and not on histo-
logical findings. Second, this study was retrospective, pa-
tient characteristics were heterogeneous making it difficult
to interpret differences in PFS and OS. However, the onset
of pulmonary toxicity is easy to detect, and its frequency
and severity might not therefore differ significantly from
those found upon prospective evaluation. Third, although
the retrospective analysis of pemetrexed-associated pul-
monary toxicity is one of the reasonable tools to assess
this issue, the small number of patients suffering from
ILD also does not allow to make definite conclusions
about clinical endpoints such as PFS and OS.

Conclusion

This is the first study to evaluate and compare the safety
and efficacy of PEM monotherapy between NSCLC pa-
tients with IIPs and without ILD. Our findings suggest
that the risk of pulmonary toxicity is higher for patients
with IIPs than those without ILD, and that the risk of
pulmonary toxicity might be higher for NSCLC patients

Table 6 Previous reports of PEM-induced ILD and our cases

A/G

Before
PEM CT
findings

Histology

Post
RTx

Pre Chemotherapy

Combination
therapy

No. of
cycle

Treatment

Outcome

Reference

1

65/M

UIP

MPM

No

None

CBDCA

1

Steroid Pulse

Dead

[17] S Sakamoto et al

2

66/F

None

NSCLC (Ad)

No

CDDP + VNR

CDDP

4

Steroid (oral)

Recover

[19] HO Kim. et al

3

71/M

None

MPM

No

None

CDDP

1

Steroid Pulse

Dead

[18] K Nagata. et al

4

77/M

None

MPM

No

None

CBDCA

1

Steroid Pulse

Dead

[18] K Nagata. et al

5

72/F

None

NSCLC (Ad)

No

CBDCA + PEM

CBDCA

2

Steroid (oral)

Recover

[20] B Dhakal. et al

6

64/M

RTx-P

NSCLC (Ad)

Yes

CBDCA + VP- 16

None

2

Steroid Pulse

Dead

[21] A Hochstrasser. et al

7

51/M

RTx-P

NSCLC (Ad)

Yes

CDDP + DTX

None

2

Steroid Pulse

Recover

[21] A Hochstrasser.
et al. 2012

8

69/M

None

NSCLC (Ad)

No

CBDCA + GEM

None

1

Steroid Pulse

Recover

[22] KH Kim et al

1

64/M

UIP

NSCLC (Ad)

No

CBDCA + PTX + BEV

None

2

Steroid Pulse

Dead

Our case

2

71/M

UIP

NSCLC (Ad)

No

None

None

1

Steroid Pulse

Recover

Our case

3

68/M

GGO

NSCLC (Ad)

No

CBDCA + PTX

None

2

Steroid Pulse

Dead

Our case

4

67/F

None

NSCLC (Ad)

No

CBDCA + PTX, DTX,
Gefitinib,

None

3

Drug
withdrawn

Recover

Our case

PEM: Pemetrexed, A/G: Age/Gender, UIP: Usual Interstitial Pneumonitis, GGO: Groud Grass Opacity, NSCLC: Non Small Cell Lung Cancer, Ad: Adenocarcinoma, PS:
performance Status, RTx: Radiation Therapy, RTX-p: radiation pneumonitis, VNR: Vinorelbine, CBDCA: Calboplatin, PTX: Paclitaxel, BEV: Bevacizmab,VP-16: Etoposide,
DTX: Docetaxel, GEM: Gemcitabine, UK: Unknown, MPM: Malignancy Pleural Mesotelioma.

Kato et al. BMC Cancer 2014, 14:508 Page 8 of 8

http://www.biomedcentral.com/1471-2407/14/508

with UIP pattern than non-UIP pattern on pretreatment
chest CT. We suggest therefore that particular care
should be taken when administering PEM to NSCLC pa-
tients with IIPs, especially those with a UIP pattern, al-
though the risk of pulmonary toxicity is not significantly
higher than when administering other chemotherapeutic
agents, for examples DTX.

Competing interests

The authors have no conflict of interest to declare.
Authors' contributions

MK and TS conceived and designed the experiments. TS, FT, RK and KT
performed the experiments. MK, TS and KM analyzed the data. MK, TS and
RK had reviewed pretreatment CT. KS, TA, RK, YH, KM, KS, RS, RK, and NS
contributed for acquisition of clinical data and specimens. TS, FT and TK
participated in management and statistical analysis of data. MK wrote the
manuscript. TS involved in revising the manuscript. KT provided final
approval of the version to be published. All authors read and approved the
final manuscript.

Acknowledgements

We thank Anurag Goel provide medical writing services on behalf of Cactus
Communications Inc.

Author details

department of Respiratory Medicine, Juntendo University Graduate School
of Medicine, 2-1-1, Hongo, 113-8421 Bunkyo-ku, Tokyo, Japan. 2 Clinical Trial
Coordination Office, Shizuoka Cancer Center, 1007 Shimonagakubo,
Nagaizumi-cho, 41 1-8777 Suntou-gun, Shizuoka, Japan.

Received: 6 January 2014 Accepted: 30 June 2014
Published: 10 July 2014

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doi:1 0.1 1 86/1 471 -2407-1 4-508

Cite this article as: Kato et al.: Pemetrexed for advanced non-smal
lung cancer patients with interstitial lung disease. BMC Cancer

2014 14:508.

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